Treatment with granulocyte-colony stimulating factor in patients with acute myocardial infarction. Evidence for a stimulation of neovascularization and improvement of myocardial perfusion.

BACKGROUND: Stem cell therapy has been suggested to be beneficial in patients after acute myocardial infarction (AMI). Strategies of treatment are either a local application of mononuclear bone marrow cells (BMCs) into the infarct-related artery or a systemic therapy with the granulocyte-stimulating factor (G-CSF) to mobilize BMCs. Nevertheless, the mechanisms responsible for improvement of cardiac function and perfusion are speculative at present. This study has been performed to investigate the effect of G-CSF on systemic levels of vascular growth factors and chemokines responsible for neovascularization, that might help to understand the positive effects of a G-CSF therapy after AMI. METHODS AND RESULTS: Five patients in the treatment group and 5 patients in the control group were enrolled in this study. The patients in the treatment group received 10 microg/kg bodyweight/day of G-CSF subcutaneously for a mean treatment duration of 6.6 +/- 1.1 days. In both groups, levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and monocyte chemotactic protein-1 (MCP-1) were measured on day 2 to 3 and day 5 after AMI. The regional wall perfusion and the ejection fraction (EF) were evaluated before discharge and after 3 months with ECG-gated MIBI-SPECT and radionuclide ventriculography, respectively. Significant higher levels of VEGF (p < 0.01), bFGF (p < 0.05) and MCP-1 (p < 0.05) were found in the treatment group compared to the control group. Levels of VEGF and bFGF remained on a plateau during the G-CSF treatment and decreased significantly in the control group. The wall perfusion improved significantly within the treatment group and between the groups (p < 0.05), respectively. The EF improved significantly within the treatment group (p < 0.05), but the change of the EF between the groups was not significant. CONCLUSION: In patients with AMI, the treatment with G-CSF modulates the formation of vascular growth factors that might improve neovascularization and result in an improved myocardial perfusion and function.

Creatine supplementation improves muscle strength in patients with congestive heart failure.

BACKGROUND: Both, cardiac and skeletal muscle creatine levels are depressed in patients with congestive heart failure (CHF). Oral supplementation of creatine (Cr) could increase physical performance in healthy volunteers. We therefore hypothesized that oral creatine supplementation improves skeletal muscle strength, quality of live and symptom-limited performance in patients with CHF. METHODS: In a double-blind, placebo-controlled and crossover-designed study, 20 patients suffering from congestive heart failure more than 6 months and a peak oxygen uptake (peak VO2) below 20 ml/min/kg received 4 x 5 g Cr daily vs. placebo for 6 weeks and were crossed over for the following 6 weeks. Peak VO2, VO2 at the anaerobic threshold (VO2AT), ejection fraction (EF), distance in 6-minute-walk-test (6 min W), and muscle strength (Modified Sphygmomanometer (MS)) were determined at baseline, after 6, and after 12 weeks. Dyspnoea after 6-minute-walk-test was measured using the Borg Scale. Quality of live was assessed with the Minnesota Living with Heart Failure Questionnaire (MLHFQ). RESULTS: 13 of 20 Patients finished the study. After 6 weeks of creatine supplementation there was a significant increase in body weight and muscle strength compared to baseline and placebo (p < 0.05). However, there was no significant change in peak VO2, VO2AT, walking distance, quality of life assessment and EF. CONCLUSION: Short-term creatine supplementation inaddition to standard medication in patients with CHF leads to an increase in body weight and an improvement of muscle strength. This effect is restricted to the time of supplementation.

[Mobilization of stem cells by granulocyte colony-stimulating factor for the regeneration of myocardial tissue after myocardial infarction]. / Mobilisation von Stammzellen durch den Granulozyten-Kolonie stimulierenden Faktor zur Regeneration myokardialen Gewebes nach Herzinfarkt.

BACKGROUND AND OBJECTIVE: Animal data suggest that mobilized bone marrow cells (BMC) may contribute to tissue regeneration after myocardial infarction (MI). However the safety, feasibility and efficacy of treatment with granulocyte colony-stimulating factor (G-CSF) to mobilize BMC after acute myocardial infarction in patients is unknown. We analysed cardiac function and perfusion in 5 patients who were treated with G-CSF in addition to standard therapeutical regimen. METHODS AND RESULTS: 48 h after successful recanalization and stent implantation in 5 patients with acute MI, the patients received 10 micro g/kg bodyweight/day G-CSF subcutaneously for a mean treatment duration of 7.6+/-0.5 days. Peak value of CD34 (+) cells, a multipotent subfraction of bone marrow cells, was reached after 5.0+/-0.7 days. After 3 months of follow-up global left ventricular ejection fraction (determined by radionuclid-ventriculography) increased significantly from 42.2+/-6.6 % to 51.6+/-8.3 % (P<0.05). The wall motion score and the wall perfusion score (determined by ECG gated SPECT) decreased from 13.5+/-3.6 to 9.9+/-3.5 (P<0.05) and from 9.6+/-2.9 to 7.0+/-4.5 (P<0.05), respectively, indicating a significant improvement of myocardial function and perfusion. No severe side effects of G-CSF treatment could be observed. Malignant arrhythmias were not observed either. CONCLUSION: In patients with acute MI, treatment with G-CSF to mobilize BMC appears to be well tolerable under clinical conditions. Improved cardiac function and perfusion may be attributed to BMC-associated promotion of myocardial regeneration and neovascularization.

Exercise capacity and Doppler pressure measurements in symptomatic peripheral arterial obstructive disease.

BACKGROUND: Doppler pressure measurements are a useful diagnostic tool in peripheral arterial obstructive disease. The aim of our study was to determine whether these pressure values do predict the degree of impairment of the walking capacity in symptomatic patients. PATIENTS AND METHODS: We compared the claudication distances (CDI: initial claudication distance, CDA: absolute claudication distance) of 939 patients (63 +/- 11 years) with stable intermittent claudication (Fontaine IIb) with the ankle pressure values at rest (APR) and after exercise (APE), with the ankle/brachial pressure index at rest (ABIR) and after exercise (ABIE), and with the ratio (ABIRATIO = ABIE/ABIR). Ankle systolic pressures were obtained using an 8 MHz Doppler probe. CD was measured by a treadmill test at constant-load conditions (3 km/hr; inclination 12%). Brachial systolic pressures were obtained using an automated blood pressure monitor. The values of the objectively worse leg were correlated with CDI and CDA. RESULTS: Low Doppler pressure values were not accompanied by significantly shorter walking distances in symptomatic patients. The resting pressure values (APR, ABIR) did not correlate with the claudication distances (CDI: 54 +/- 31 m; CDA: 87 +/- 41 m). For the exercise values (APE, ABIE), even a very slight inverse correlation with the claudication distances was found. In addition, the correlation between the pressure index ratio and the walking distances (ABIRATIO vs. CDI: r = -0.25, p < 0.01; ABIRATIO vs. CDA: r = -0.20, p < 0.01) was inverse, too, but slightly more pronounced. CONCLUSIONS: In patients with intermittent claudication the ankle artery pressures and the indices derived from these pressure values do not predict the walking distance. Therefore, the decision for angioplasty or bypass surgery should be made with regards to the impairment of quality of life rather than Doppler pressure values.

[Leptin: a parameter for metabolic changes in heart failure]. / Leptin: Ein Parameter für metabolische Veränderungen der Herzinsuffizienz.

OBJECTIVE: Advanced chronic heart failure is a hypercatabolic state with an imbalance between anabolic and catabolic metabolism and finally progressive loss of both muscle mass and adipose tissue. Leptin, the product of the obesity gene, is a hormone secreted by adipocytes. Therefore, we tested the hypothesis that plasma leptin concentrations are reduced in advanced chronic heart failure. METHODS: In 20 patients with chronic congestive heart failure (LVEF 23 +/- 6%) and 20 healthy controls (LVEF 65 +/- 8%) matched for gender, age, and body mass index, fasting plasma leptin (ELISA) and TNF alpha (ELISA) were measured. Follow-up examination was performed after 1 year. RESULTS: The fasting plasma leptin concentrations of patients with NYHA grade III (8.4 +/- 3.8 ng/ml*) and NYHA grade IV (4.6 +/- 2.4 ng/ml dagger) were significantly lower as compared with the controls (11.2 +/- 3.1 ng/ml; *p < 0.05, dagger p < 0.01). In patients with NYHA grade II plasma leptin levels were significantly elevated as compared with the healthy controls (14.9 +/- 4.2 ng/ml). TNF alpha was higher in heart failure patients than in healthy controls (8.6 +/- 3.6 pg/ml; 5.9 +/- 2.1 pg/ml; respectively; p < 0.05), but did not correlate with the NYHA functional class. Mortality of the controls was 0%, whereas 15% (n = 3) in the congestive heart failure group; one patient (5%) needs an urgent heart transplantation. All of those patients had leptin concentrations below 5 ng/ml. CONCLUSIONS: Plasma leptin concentrations correlate with the NYHA functional class suggesting anabolic metabolism in NYHA class II and catabolic metabolism in advanced heart failure which might be of prognostic relevance.

[Cardiac manifestations of peripheral primitive neuroectodermal tumor (pPNET): a rare case]. / Kardiale Manifestation eines peripheren primitiven neuroektodermalen Tumors (pPNET)--eine Rarität.

HISTORY: A 44-year-old man presented to his general practitioner with increasing exertional dyspnoea. After a syncope he was admitted to hospital. INVESTIGATIONS: Echocardiography on admission demonstrated a large pericardial effusion (45 mm over the right and 57 mm over the left ventricle) which, in view of its haemodynamic relevance, had to be removed by pericardiocentesis. Cytological examination of the fluid showed various blood constituents but no atypical cells. Computed tomography (CT) of the thorax revealed a homogeneous hyperdense structure in the area of the left atrium. After several more pericardiocenteses echocardiography showed a pericardial tumour between the left atrium and ventricle. Gastroscopy, coloscopy, abdominal CT, an octreotide scan and positron-emission tomography did not indicate an extracardiac tumour. Coronary angiography and video-assisted thoracoscopy were performed. They confirmed an epicardial tumour at the level of the left atrium. TREATMENT AND COURSE: The entire round and solid tumour of about 3 cm in diameter, at the tip of the left atrial appendage was removed under extracorporeal circulation. No adjuvant treatment was given. Histological and immunohistological tests of the resected specimen (CD-99 and NSE-positive) provided the diagnosis of malignant peripheral primitive neuroectodermal tumour (pPNET). CONCLUSION: There are at present no adequate data on optimal treatment of pPNET in the heart. This case demonstrates that even with a large such tumour long remission is possible after complete removal without any adjuvant treatment.